COVID19 SARS Vaccinations: Systemic Allergic Reactions to SARS-CoV-2 Vaccinations

This is a multicenter, randomized, initially blinded (masked), phase 2 trial to assess SARS-CoV-2 vaccination reactions in two populations:

• One population including individuals with a history of allergic reactions or Mast Cell Disorder (HA/MCD), and
• One comparison population without severe allergies or mast cell disorders.

Approximately 2040 HA/MCD and 1360 comparison participants will be enrolled across participating sites in the United States. Approximately two-thirds of participants enrolled in each of the 2 groups will be female. This is because the vast majority of cases of anaphylaxis to the COVID-19 vaccines have occurred in women. Enrollment of participants who qualify only on the basis of reactions to multiple unrelated drugs will be limited to approximately 300.

Enrollment of the MCD group is anticipated to be at least 200 participants, and not more than 300 participants.

Participants in each population will be randomized 2:2:1:1 to receive the Pfizer-BioNTech COVID-19 Vaccine, Moderna COVID-19 Vaccine, placebo + Pfizer-BioNTech COVID-19 Vaccine, or placebo + Moderna COVID-19 Vaccine, if enrolled in the initial study period under protocol versions 1.0 -4.0. Participants enrolled under protocol version 5.0 will be randomized 2:1 to receive the Pfizer-BioNTech COVID-19 Vaccine or placebo + Pfizer-BioNTech COVID-19 Vaccine. If enrollment under protocol version 5.0 is robust and sustained, the active vaccine randomization may be changed to the Moderna COVID-19 Vaccine.

Participants randomized to one of the placebo groups will receive placebo as a first dose and will receive two doses of their assigned active vaccine at subsequent visits. During the first visit, all participants will be initially-blinded to whether they are receiving placebo or vaccine, and to which vaccine they are receiving (if enrolling under protocol versions 1.0 -4.0).

Due to the different dosing schedules for the Pfizer-BioNTech COVID-19 Vaccine and Moderna COVID-19 Vaccine, it will become apparent to both the site staff and the study participant which vaccine has been assigned, once the second injection visit is scheduled. However, the blind over placebo versus vaccine will remain in effect until after the second visit. During a follow-up call, scheduled 3 days after the second injection, participants will be unblinded as to whether they received placebo or active vaccine.

However under protocol version 5.0, participants will be told if they received placebo as the first injection during the following up conducted 3 days after. Participants in this phase of the study will also know which company's vaccine they are receiving, as the vaccines are anticipated to be used sequentially and will also be noted in the consent form.

Study Duration: Randomized and vaccinated participants will complete study participation in approximately 29 days if vaccinated with the Pfizer-BioNTech COVID-19 Vaccine, 36 days if vaccinated with the Moderna COVID-19 Vaccine. Participants enrolled under protocol versions 1.0 -4.0 will complete study participation in 50 or 64 days if administered placebo before receiving two doses of either the Pfizer-BioNTech COVID-19 Vaccine or the Moderna COVID-19 Vaccine, respectively and participants enrolled under protocol version 5.0 will complete participation in approximately 36 of 43 days, respectively, if they receive placebo first.

Inclusion criteria

Individuals who meet all of the following criteria are eligible for enrollment as study participants:

Both groups (e.g., High-Allergy and Mast Cell Disorder (HA/MCD) Group and Comparison Group):

• Able to understand and provide informed consent
• Male or non-pregnant female ≥12 years of age on the date of first study vaccination/placebo administration (protocol versions 1.0 - 4.0) OR male or non-pregnant female 5-17 years of age on the date of first study vaccination/placebo administration (protocol version 5.0)
• Females of childbearing potential must have a negative pregnancy test prior to the first vaccination and placebo administration, if applicable.

--If a participant becomes pregnant after receiving a placebo dose but prior to receiving study vaccination, she will be discontinued from the study

• Females of reproductive potential° and sexually active must agree to use FDA approved methods of birth control for the duration of the study. These include hormonal contraceptives, intrauterine device, double barrier contraception (i.e., condom plus diaphragm), or male partner with documented vasectomy.

• Menopause is defined as at least 12 consecutive months without menses; if in question, a follicle stimulating hormone of ≥25 U/mL must be documented.
• Hysterectomy, bilateral oophorectomy, or bilateral tubal ligation must be documented, as applicable; if documented, women with these conditions are not required to use additional contraception.

High-Allergy and Mast Cell Disorder (HA/MCD) Group:

Individuals who meet at least one of the following criteria are eligible for enrollment in the HA/MCD group:

• History of a severe allergic reaction to food(s), allergen immunotherapy, insect venom(s), or latex with use of epinephrine within the last 15 years
• History of an Emergency Department visit with convincing evidence of a systemic allergic reaction (consistent with CoFAR Grade 3 or higher) to food(s), allergen immunotherapy, insect venom(s), or latex within the last 15 years
• History of documented, immediate allergic reactions to 2 or more unrelated drugs within the last 15 years
• A convincing clinical history, or a history that is accompanied by a positive skin test, of an immediate reaction to a drug, vaccine, or latex within the last 15 years
• History of physician-diagnosed idiopathic anaphylaxis requiring epinephrine or an Emergency Department visit in the last 15 years
• History of a physician-diagnosed mast cell disorder (e.g., mastocytosis, mast cell activation syndrome [MCAS], or hereditary alpha-tryptasemia). MCAS must meet consensus criteria as defined below:

• Criterion A: Typical clinical signs of severe, recurrent (episodic) systemic Mast Cell Activation are present (often in form of anaphylaxis)

---Definition of systemic: involving at least 2 organ systems

• Criterion B: Involvement of Mast Cell (MC) is documented by biochemical studies

--- Preferred marker: increase in serum tryptase level from the individual's baseline to plus 20% + 2 ng/ml

• Criterion C: Response of symptoms to therapy with MC-stabilizing agents, drugs directed against MC mediator production or drugs blocking mediator release or effects of MC-derived mediators
• NOTE: All 3 Mast Cell Activation Syndrome (MCAS) criteria (A + B + C) must be fulfilled to call a condition MCAS.

Comparison Group:

Individuals who meet all of the following criteria are eligible for enrollment in the comparison group:

• No history of allergic asthma or atopic dermatitis within the last 10 years
• No history of chronic spontaneous urticaria, or angioedema
• No history of allergic reactions to foods or insect venoms
• No history of allergic reactions to drugs or vaccines
• No history of anaphylaxis
• No history of a mast cell disorder (e.g., mastocytosis, mast cell activation syndrome [MCAS], or hereditary alpha- tryptasemia)

Exclusion criteria

Individuals who meet any of these criteria are not eligible for enrollment as study participants:

• Inability or unwillingness of a participant and/or parent/legal guardian to give written informed consent and/or assent, as applicable, or to comply with study protocol
• Weight less than 15 kg (33 lbs)
• Prior receipt of any doses of the Pfizer-BioNTech coronavirus disease 2019 (COVID-19) Vaccine, Moderna COVID-19 Vaccine, or any other COVID-19 vaccine
• History of a severe reaction to any component of the Pfizer-BioNTech COVID-19 Vaccine or Moderna COVID-19 Vaccine
• History of contact dermatitis with confirmed patch test reaction to Prevalence of polyethylene glycol (PEG)
• History of reaction to Doxil®
• Known exposure to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and still within the quarantine window
• Symptoms consistent with acute COVID-19 infection or known COVID-19 infection (positive Polymerase chain reaction [PCR] or antigen test) and still within the quarantine window
• Have an acute illness, including body temperature greater than 100.4 degrees Fahrenheit, within 14 days of the first study vaccination/placebo administration or 3 days prior to each subsequent vaccination
• History of autoimmune or other disorders requiring systemic immune modulators
• History of acute urticaria within 28 days of randomization
• Pregnant
• Have received any vaccines within 14 days of the first study vaccination/placebo administration or plan to receive other vaccines during the study period
• Had any allergen immunotherapy administration within 24 hours prior to vaccination/placebo administration or plan to receive within 24 hours after vaccination/placebo administration
• Have received a biologic therapy within 6 months of randomization
• Use of systemic steroids for any reason within 28 days of randomization
• Use of Zileuton® within 14 days of randomization
• Use of any monoclonal antibody agent for treatment or prevention of COVID-19 within 3 months of randomization
• Coronary artery disease, peripheral or cerebral vascular disease, unstable angina, or cardiac arrhythmia, other than supraventricular tachycardia (SVT)
• Medically unstable hypertension
• Current use of beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, monoamine oxidase (MAO) inhibitors, tricyclic anti-depressants or other agents that could interfere with the treatment of anaphylaxis, in the opinion of the investigator
• Unstable asthma within 3 months of randomization or symptomatic asthma on the day of vaccination, as assessed by the site investigator
• Have past or current medical problems or findings from physical exam or laboratory testing not listed above, which in the opinion of the investigator, may pose additional risks from participation in the study or which may interfere with the ability to comply with study requirements --This includes individuals with underlying conditions or other medications that, in the opinion of the investigator, may increase risk in the event of an anaphylactic reaction or lead to complications following administration of epinephrine